Synergism and Antagonism of Two Distinct, but Confused, Nrf1 Factors in Integral Regulation of the Nuclear-to-Mitochondrial Respiratory and Antioxidant Transcription Networks.
Synergism and Antagonism of Two Distinct, but Confused, Nrf1 Factors in Integral Regulation of the Nuclear-to-Mitochondrial Respiratory and Antioxidant Transcription Networks.
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两个不同但混淆的 Nrf1 因子在核线粒体呼吸和抗氧化转录网络整体调节中的协同和拮抗作用
DOI：
10.1155/2020/5097109
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发表时间：
2020
影响因子：
--
通讯作者：
Zhang Y
中科院分区：
文献类型：
--
作者：
Zhang S;Deng Y;Xiang Y;Hu S;Qiu L;Zhang Y
迄今为止，还没有文献能够解释两种截然不同且令人困惑的Nrf1转录因子，因为它们与核因子红系2相关因子1（也称为Nfe2l1）和核呼吸因子（最初称为α-Pal）有相同的缩写。因此，我们在这里确定了Nfe2l1Nrf1和α-PalNRF1在核到线粒体呼吸和抗氧化转录谱的综合调节中发挥协同和拮抗作用。在小鼠胚胎成纤维细胞（MEFs）中，敲除Nfe2l1−/−导致α-PalNRF1和Nfe2l2以及TFAM（线粒体转录因子A）和其他靶基因的表达水平显著降低。Nfe2l1−/−mef中也有类似的抑制结果，但GSTa1和Aldh1a1在Nfe2l1−/−mef中均明显上调。在Keap1−/−mef中证实了Nfe2l1和Nfe2l2对α-PalNRF1和TFAM的正向调节的协同作用。然而，hNfe2l1α−/−、hNfe2l2-/-ΔTA甚至hNfe2l1α−/−+siNrf2均未改变人α-PalNRF1的表达，尽管TFAM被Nfe2l1激活，但被Nfe2l2抑制；这种拮抗作用发生在HepG2细胞中。相反，在α-PalNRF1+/- mef中，几乎所有小鼠Nfe2l1、Nfe2l2和共靶基因均下调表达。相反，人Nfe2l1、Nfe2l2及相关报告基因在α-PalNRF1沉默后上调，而α-PalNRF1异位表达后下调。此外，除α-PalNRF1外，Pitx2 （pituitary homeobox 2）也被鉴定为Nfe2l1和TFAM的直接上游调节因子。总的来说，这些Nfe2l1、Nfe2l2和α-PalNRF1之间的交叉对话，以及Pitx2，从内质网整合到针对TFAM的核-线粒体通信，以便精细调节不同细胞氧化呼吸和抗氧化基因转录网络的强大平衡，尽管它们在小鼠和人类之间有所不同。此外，需要特别注意的是，鉴于这些转录因子的相互调节作用，对于敲除Nfe2l1、Nfe2l2、α-Pal或Pitx2或其功能获得突变体所获得的相关实验结果，我们需要非常谨慎地进行解释。
There is hitherto no literature available for explaining two distinct, but confused, Nrf1 transcription factors, because they shared the same abbreviations from nuclear factor erythroid 2-related factor 1 (also called Nfe2l1) and nuclear respiratory factor (originally designated α-Pal). Thus, we have here identified that Nfe2l1Nrf1 and α-PalNRF1 exert synergistic and antagonistic roles in integrative regulation of the nuclear-to-mitochondrial respiratory and antioxidant transcription profiles. In mouse embryonic fibroblasts (MEFs), knockout of Nfe2l1−/− leads to substantial decreases in expression levels of α-PalNRF1 and Nfe2l2, together with TFAM (mitochondrial transcription factor A) and other target genes. Similar inhibitory results were determined in Nfe2l2−/− MEFs but with an exception that both GSTa1 and Aldh1a1 were distinguishably upregulated in Nfe2l1−/− MEFs. Such synergistic contributions of Nfe2l1 and Nfe2l2 to the positive regulation of α-PalNRF1 and TFAM were validated in Keap1−/− MEFs. However, human α-PalNRF1 expression was unaltered by hNfe2l1α−/−, hNfe2l2-/-ΔTA, or even hNfe2l1α−/−+siNrf2, albeit TFAM was activated by Nfe2l1 but inhibited by Nfe2l2; such an antagonism occurred in HepG2 cells. Conversely, almost all of mouse Nfe2l1, Nfe2l2, and cotarget genes were downexpressed in α-PalNRF1+/- MEFs. On the contrary, upregulation of human Nfe2l1, Nfe2l2, and relevant reporter genes took place after silencing of α-PalNRF1, but their downregulation occurred upon ectopic expression of α-PalNRF1. Furtherly, Pitx2 (pituitary homeobox 2) was also identified as a direct upstream regulator of Nfe2l1 and TFAM, besides α-PalNRF1. Overall, these across-talks amongst Nfe2l1, Nfe2l2, and α-PalNRF1, along with Pitx2, are integrated from the endoplasmic reticulum towards the nuclear-to-mitochondrial communication for targeting TFAM, in order to finely tune the robust balance of distinct cellular oxidative respiratory and antioxidant gene transcription networks, albeit they differ between the mouse and the human. In addition, it is of crucial importance to note that, in view of such mutual interregulation of these transcription factors, much cautions should be severely taken for us to interpret those relevant experimental results obtained from knockout of Nfe2l1, Nfe2l2, α-Pal or Pitx2, or their gain-of-functional mutants.
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DOI：
10.1016/j.bbrc.2003.12.065
发表时间：
2004-01-30
影响因子：
3.1
作者：
Choi, YS;Kim, S;Pak, YK
通讯作者：
Pak, YK
影响因子：
56.9
作者：
HWANG, C;SINSKEY, AJ;LODISH, HF
通讯作者：
LODISH, HF
影响因子：
4.6
作者：
Lee WR;Na H;Lee SW;Lim WJ;Kim N;Lee JE;Kang C
通讯作者：
Kang C
影响因子：
64.5
作者：
Hillen HS;Morozov YI;Sarfallah A;Temiakov D;Cramer P
通讯作者：
Cramer P
影响因子：
7.2
作者：
Gray, Michael W.
通讯作者：
Gray, Michael W.